High density lipoprotein cholesterol (HDL-C) levels are thought to protect against cardiovascular disease. This may or may not be true in certain populations. The long-term goal of this research project is to determine if a deficiency in the lipoprotein receptor, scavenger receptor class B type I or SR-BI, is a cause of high levels of HDL-C and, perhaps paradoxically, an increased risk for cardiovascular disease. In specific aim 1, we will perform in vitro experiments to examine the mechanism(s) by which certain SR-BI gene (SCARB1) variants affect SR-BI protein expression. In specific aim 2, we will continue recruiting subjects with HDL-C levels above 60 mg/dl (this is because levels above 60 mg/dl are thought to be cardioprotective) and obtaining blood specimens to measure cholesterol levels, DNA, and monocyte-derived macrophage that express SR-BI protein. We will examine the association of genetic variations within the SCARB1 gene with lipid levels, macrophage SR-BI protein and RNA expression and SR-BI function (as measured by the uptake of cholesteryl esters from radiolabeled HDL). We will also examine the association of SCARB1 polymorphisms and lipid levels and subclinical atherosclerosis in participants of the Multi-Ethnic Study of Atherosclerosis (MESA) and in subjects with premature myocardial infarction (Myocardial Infarction Genetics Consortium Study). The results from our studies will provide further insight into the role of SR-BI on lipid levels and cardiovascular disease in subjects with elevated levels of HDL-C, in a larger population (MESA) well-represented by persons of Caucasian, African-American, Hispanic and Asian ancestry, and in subjects with premature myocardial infarction.